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Despite advances in cancer genomics and the increased use of genomic medicine, metastatic cancer is still mostly an incurable and fatal disease. With diminishing returns from traditional drug discovery strategies, and high clinical failure rates, more emphasis is being placed on alternative drug discovery platforms, such as ex vivo approaches. Ex vivo approaches aim to embed biological relevance and inter-patient variability at an earlier stage of drug discovery, and to offer more precise treatment stratification for patients. However, these techniques also have a high potential to offer personalised therapies to patients, complementing and enhancing genomic medicine. Although an array of approaches are available to researchers, only a minority of techniques have made it through to direct patient treatment within robust clinical trials. Within this review, we discuss the current challenges to ex vivo approaches within clinical practice and summarise the contemporary literature which has directed patient treatment. Finally, we map out how ex vivo approaches could transition from a small-scale, predominantly research based technology to a robust and validated predictive tool. In future, these pre-clinical approaches may be integrated into clinical cancer pathways to assist in the personalisation of therapy choices and to hopefully improve patient experiences and outcomes.

We examined developmental changes in children's inductive inferences about biological concepts as a function of knowledge of properties and concepts. Specifically, 4- to 5-year-olds and 9- to 10-year-olds were taught either familiar or unfamiliar internal, external, or functional properties about known and unknown target animals. Children were asked to infer whether each of four probes, varying in categorical and perceptual similarity to the target, also shared that property. Overall, children made more inferences for known concepts and familiar properties. Older children were more likely to use categorical than perceptual information when making inferences about internal and functional properties of known concepts; however, younger children, in general, made no distinction for property type, and they weighted categorical and perceptual information similarly. Both age groups utilized appearance when making inferences about external properties. Results are discussed in terms of developmental changes in children's appreciation of essentialism. Copyright © 2010 John Wiley & Sons, Ltd.

I nfliximab (Remicade, Centocor Inc.) is a monoclonal antibody, cA2, targeted against tumor necrosis factor-alpha (TNF) approved for the treatment of Crohn’s disease and rheumatoid arthritis. The mechanism of infliximab is to specifically inhibit the activity of TNFthrough the neutralization of the proinflammatory cytokine. The drug is able to bind to the transmembrane receptor and thus inhibit the inflammatory effects of TNF. Furthermore, the cells that have infliximab bound to the cellular receptors can be lysed in vitro by complement. By decreasing the levels of TNF, there is a decrease in the inflammatory response and immune reaction. By decreasing the levels of TNFin patients with Crohn’s disease, signs and symptoms of the disease, including fistulas, have significantly improved. Infliximab is FDA approved for both induction and maintenance of remission of Crohn’s disease. Reported adverse reactions to infliximab include respiratory tract infections, including cough, sinusitis, pharyngitis, and bronchitis, nervous system effects, including headache, dizziness, and pain, musculoskeletal effects, including arthralgias and back pain, abdominal pain, including nausea and diarrhea, and chills and fever. Hypersensitivity reactions consisting of dyspnea, urticaria, and hypotension occur in approximately 10 percent of patients. Another complication of infliximab treatment is the reactivation of latent tuberculosis. By decreasing the immune response, tuberculosis can become symptomatic. A potential side effect of an immune modifying medication is the possibility of initiating a malignancy. The most commonly reported malignancy is lymphoproliferative disorder. In a report evaluating infliximab, nine patients reportedly developed a lymphoproliferative disorder, eight of which were lymphomas. It is unclear whether infliximab contributes to malignancy or whether the patient’s disease condition itself leads to the malignancy. A few studies have indicated a possible association between infliximab therapy for Crohn’s disease and the onset of lymphoma. However, a review of the literature did not produce any studies or case reports of infliximab treatment for Crohn’s disease associated with adenocarcinoma of the colon and colonic metastasis. We Correspondence to: Guy R. Orangio, M.D., Georgia Colon and Rectal Surgical Clinics, 5555 Peachtree Dunwoody Road, Suite 206, Atlanta, Georgia 30342, e-mail: gorangio@gcrsa.com Dis Colon Rectum 2005; 48: 1651–1655 DOI: 10.1007/s10350-005-0065-1 © The American Society of Colon and Rectal Surgeons Published online: 13 May 2005

Children's memory for a specific episode of a repeated event was investigated in 2 experiments. In Experiment 1, eighty 4- and 7-year-olds experienced a standard novel event 1, 2, or 4 times, followed by an episodic event for those children who had multiple standard event experiences. The episodic event involved the addition of both schema-typical and schema-atypical activities to the standard event. Following a 1-week delay, children were asked to recall both event types. Four-year-olds were more confused than older children regarding when the new activities had been experienced, although experience improved memory for the schema-atypical activities. In contrast, 7-year-olds were able to establish more accurate memories for both the schema-typical and the schema-atypical changes. Experiment 2 demonstrated that 4-year-olds could, however, establish distinct memories for both types of changes when the standard event was simplified. The results are discussed in terms of the development of the relation between script memory and memory for a specific instance of an event.

Several cases of long term radiation sequelae have been reported in patients with lupus erythematosus and systemic sclerosis after breast or chest wall irradiation. To the authors' knowledge, no experience with such complications in patients with mixed connective tissue disease (MCTD) has been reported previously.A case of a woman with occult breast carcinoma metastatic to the axilla and preexisting MCTD is presented. To the authors' knowledge, this is the first case report of the adverse effects of breast irradiation in a patient with MCTD. The pathophysiology of such radiation injury to specific anatomic structures and technical dosimetric considerations of the radiation therapy and radiation dose are analyzed. The relevant literature on other collagen vascular diseases with features related to MCTD is reviewed.A moderate dose of radiation to the breast and regional lymphatics resulted in marked early and late toxicity to skin and subcutaneous tissues. The tissue injury was similar to that observed in patients with lupus erythematosus and systemic sclerosis. The early skin reaction (moist desquamation) was related to the daily radiation dose delivered at the depth of the epidermis, and the late reaction (subcutaneous fibrosis) was related to the dose at the depth of the dermal capillaries and dermal connective tissue.Patients with MCTD may develop exaggerated radiation reactions similar to those in patients with lupus erythematosus and systemic sclerosis. Although the incidence of such radiation reactions in patients with MCTD is difficult to assess, the risks and benefits of radiation therapy should be carefully weighed in these patients, particularly if an alternative therapy is available. If there is no alternative, judicious attention to radiotherapy technique may reduce or prevent skin toxicity.

Depth dose characteristics of 24-MV beams from a medical linear accelerator at various SSDs have been measured. The dose buildup, percent depth dose (PDD), and output were measured using ionization chambers and a diode detector under full scatter. Surface dose ranged from 8% to 51% depending upon the collimator setting at 100-cm SSD. It decreased by 10%-15% as distance was increased to 200 cm, but remained unchanged beyond this distance. The dmax migrated rapidly toward the surface with increasing field size at 100-cm SSD. At extended SSD, the dmax occurred at greater depths and shifted a little toward the shallow depths with increasing field size. Large field PDDs measured at extended SSD agreed well with those predicted from 100-cm data. The output followed the 1/(distance)2 relationship quite well. The extended SSD beam data are clinically useful when treating hemibody or performing total body irradiation (TBI) procedures.

Tissue compensators made with a high atomic number material are compact and retain the skin-sparing effect of megavoltage beams. In this note, we have described the use of a commercially available vinyl lead as a material for tissue compensators for use with 4-MV beams on a Clinac-4/80. The dosimetric data obtained included the sheet's lead equivalence, thickness ratios, surface dose and buildup region, and transmission factors. The presence of a compensator did not alter the beam's skin-sparing effects. It was concluded that the vinyl lead sheets allowed an easy and rapid fabrication of a tissue compensator for head and neck portals of up to 15 X 15 cm.

A system of coupled differential equations relates the amplitudes of alpha particle waves emitted from a spheroidal nucleus described by the Bohr–Mottelson model. These equations in spheroidal coordinates have been solved for five even–even nuclides with the aid of the electronic computer FERUT. There are four possible cases for each nuclide which are consistent with the boundary conditions. The solutions of the equations are used to calculate the probability density of alpha particles on the nuclear surface for each case. For Case I the peak in the distribution function shifts from the nuclear symmetry axis to the equator with increasing mass number. The probability density for Case II is always peaked between the symmetry axis and the equator, while for Cases III and IV it is always peaked strongly at the equator. The change in the distribution function with increasing distance from the nucleus is considered for a typical case. Barrier penetration factors are calculated and found to differ from those for spherical nuclei by factors of the order of 2 or 3. Comparison with the calculations of an approximation method of Fröman is made for one nuclide.

For interstitial implants with radioactive Au-198 seeds, the dosimetric calculations usually ignore the finite source size and employ a point source approximation, resulting in a computed isotropic dose distribution. However, the measured radiation fluence from Au-198 seeds is reported to be anisotropic, suggesting some amount of dose anisotropy in tissue. We have measured this dose anisotropy around Au-198 seeds (2.5 X 0.8 mm2) using Kodak X-OMAT XV-2 films placed in contact with individual seeds in a phantom. Autoradiographs obtained for various exposure times were digitized and studied with an image analysis computer network. The network's overall spatial resolution was about 0.01 cm. The optical isodensity contours around the seed were obtained. The useful range of optical density (OD) for the system was found to be 1 to 2 OD units. Within this range, the shape of an optical isodensity contour would be identical to an isodose contour. Proximal to the source, the contours were elliptical in shape, elongated along the seed axis. However, further away, the elongation was in the direction normal to the seed axis. This was in agreement with the reported data on the radiation fluence around Au-198 seeds. It was concluded that measurable dose anisotropy existed around Au-198 seeds. However, it was too small to be of any clinical significance.

A rotating beam splitter was designed and fabricated for use in treating tangential breast fields on an AECL Theratron-80 cobalt teletherapy unit. Its dosimetric properties were studied using a 0.6-cm3 Baldwin-Farmer ionization chamber with Keithley electrometer and a Scanditronix RFA-3 three-dimensional water phantom scanner with semiconductor detector. An aluminum plate, which held the semicircular rotating 5-HVL (half-value layer) lead block, extended to the phantom surface (80-cm source-surface distance). The beam was blocked directly along the central axis and also at distances up to 7.5 mm off-axis, corresponding to the projected extent of the 1.5-cm-diam source. The penumbra at the central ray and at each off-axis point was measured at dmax and at 5-cm depth in water. A reduction in the penumbra from 8 to about 2 mm for 20 X 20 cm2 beam was observed regardless of the off-axis distance of the block. Isodose distributions obtained for various field sizes indicated that the percent depth doses of the split fields agree well with the equivalent squares of the irradiated field sizes. Output measurements in water and in air indicated that scatter from the aluminum plate more than compensates for the reduction in backscatter factor, due to the decrease in irradiated area when the beam splitter is used. Isodose curves in various planes were obtained at clinically useful rotational angles of the beam splitter. Computer generated isodose curves have been obtained that match the measured curves to be used in treatment planning.

The leakage characteristics of electron applicators on our Clinac 2500 linear accelerator have been measured. The leakage radiation in the patient plane and at the surface of the electron applicators has been measured for applicator sizes from 6 cm X 6 cm to 25 cm X 25 cm and beam energies from 6 to 22 MeV. For certain applicator/energy combinations the leakage radiation was significant. The leakage radiation, relative to the central axis dose, was found to be up to 7% in the patient plane and up to 39% at the applicator surface. Reducing the collimator setting or adding lead at select locations on the applicator surface was effective in reducing the magnitude of the radiation leakage.

A method of spatially filtering the primary x-ray beam to emphasize the middle and upper frequency structure within a patient is under investigation. In a feasibility study, a copper filter is constructed which complements the low frequency structure of a scout film. The filter is placed in the x-ray beam and a new radiograph is taken. The result is a final x-ray in which the low frequency structures are suppressed, i.e., the middle and upper frequency structures are emphasized. This provides nearly constant detection probabilities for small, low contrast structures, regardless of their location in the patient. The results obtained from several such filters are very encouraging.© (1980) COPYRIGHT SPIE--The International Society for Optical Engineering. Downloading of the abstract is permitted for personal use only.

A preliminary report in 1965 described a conservative surgical procedure for the management of acute and chronic horseshoe anal fistulas. The operation has been used exclusively at the Ochsner Clinic for this problem since 1963. Forty-one patients were treated from 1963 to 1973. The paper reviews the pathology of acute and chronic horseshoe anal fistulas and describes the surgical procedure for both acute and chronic horseshoe abscess anal fistulas with accompanying illustrations. The excellent results with minimal deformity of the anus and anal canal are attributed to avoidance of severing the superficial external sphincter between its coccygeal origin and the anus. Of the 41 patients treated in the period from 1963 to 1973, healing was good, and there has been no recurrence.